Comparative evaluation of systemic drugs for their effects against Anopheles gambiae

Abstract

Laboratory and field studies have shown that ivermectin, a drug that targets invertebrate ligand-gated ion channels (LGICs), is potently active against Anopheles spp. mosquitoes at concentrations present in human blood after standard drug administrations; thus ivermectin holds promise as a mass human-administered endectocide that could help suppress malaria parasite transmission. We evaluated other systemic LGIC-targeting drugs for their activities against the African malaria vector Anopheles gambiae using in vitro blood feeding assays. Eprinomectin, selamectin, moxidectin, and N-tert-butyl nodulisporamide were evaluated as potentially systemic drugs having similar modes of action to ivermectin; all primarily are agonists of invertebrate glutamate-gated chloride ion channels. Additionally, nitenpyram and spinosad were evaluated as systemic drugs that primarily work as agonists of nicotinic acetylcholine receptor channels. Only eprinomectin killed Anopheles gambiae at concentrations that were comparable to ivermectin. At sub-lethal doses, nitenpyram and moxidectin marginally affected mosquito re-blood feeding ability. The macrocyclic lactones, particularly eprinomectin, caused significantly increased knockdown and significantly inhibited recovery in blood fed females. These data are a first step in evaluating drugs that might be eventually combined with, or substituted for ivermectin for future malaria parasite transmission control.

In Vitro Efficacy of Moxidectin versus Ivermectin against Sarcoptes scabiei

“…Where the filarial nematodes Brugia malayi and Dirofilaria immitis are concerned, the ivermectin IC 50 s ranged from 4.6 to 28.2 M, depending on life stage (27,29). These concentrations are generally higher than have been documented for arthropods for which ivermectin LC 50 s range from 23 nM (Cimex lectularius, Musca domestica, Anopheles gambiae) to 0.69 M (Aedes aegypti) (19,20,22). There have been few studies on mites, although one recent report shows ivermectin's extremely high activity against spider mites (Tetranychus cinnabarinus; 10.3 nM) (30).…”

“…Differences between ivermectin's and moxidectin's activities are apparent, especially against arthropods (19)(20)(21)(22). From this, questions emerge regarding the threshold for acaricidal activity of both drugs over the mite life cycle and how this relates to therapeutically relevant concentrations, bioavailability, and safety margins.…”

“…The LC 50 of moxidectin at 24 h for A. gambiae (4.2 M) is over 100-fold higher than that of ivermectin (20). In spider mites, ivermectin was 2-fold more active than milbemycin (30), although newly developed synthetic milbemycins had higher activity (0.03 to 0.17 M) (31).…”

Characterization of the target of ivermectin, the glutamate-gated chloride channel, fromAnopheles gambiae

“…These hair-like cells are connected to the basal plate of the Johnston's organ, and transduce vibrations in the antenna for audition and flight balance (Gopfert and Robert, 2002;. Importantly, we have previously reported that sub-lethal doses of IVM impair coordinated flight movement, including increased knockdown and reduced recovery, which could be the result of impairing this sensory organ (Butters et al, 2012). GluCl was present in all three neuropils of the optic lobes, which process visual signals from the compound eye and send projections to the supraesophageal ganglion (Fortini and Rubin, 1991).…”

“…More recently, IVM mass drug administration in multiple locations across West Africa has been shown to temporarily reduce the proportion of Plasmodium falciparum-infected A. gambiae in IVM-treated villages (Kobylinski et al, 2011;Alout et al, 2014). Sub-lethal doses of IVM have also been shown to inhibit the sporogony of P. falciparum in A. gambiae s.s. and impair coordinated flight patterns (Butters et al, 2012;Kobylinski et al, 2012). In clinical trials, IVM, in combination with artemether-lumefantrine, has been shown to reduce the likelihood of malaria transmission through reduction of mosquito survivorship (Ouedraogo et al, 2014).…”